IL45738A - D-homo-pregnenes,process for their preparation and pharmaceutical compositions containing them - Google Patents

Description

D-homo-pregnenes , process for their preparation and pharmaceutical compositions containing them o*¾naon mnpn 'wm onaan "j' nn ,o* 3 ans-iam- D * The invention is concerned with new, pharmacologically active D-homo steroids, a process for their manufacture, and also pharmaceutical preparations containing these compounds .

The new D-homo-steroi ds are characterised by the general formula I i which the bond ..... is a single bond or a double bond, X represents a hydrogen atom, or a fluorine atom, Y represents a hydrogen atom or a fluorine atom, and Z represents a hydroxyl group, or Y represents a chlorine atom and Z represents a hydroxyl group, a fluorine atom or a chlorine atom, R-, represents a hydrogen atom, a free hydroxyl group or one esterified with a alk o l hate or phosphate g he groupings in which R2 represents a hydrogen atom or a methyl group, R^ represents a hydroxyl group R^ represents a methyl group or a hydroxyl group 7 The new D-homo-steroi ds of the general formula I are pharmacologically active substances, which are especially distinguished by their good anti -i nfl ammatory activity and the fact that they cause only small side ef ects .

The onset and duration of the action of the new D-homo-steroi ds and also their solubility in physiologically tolerable solvents depend, as is the case with known corticoids, especially on whether a hydroxyl group in the 21-position is esterified, and if so with what acid.

As esterified 21-hydroxyl groups R-| there come into consideration lower alkanoyloxy groups, sulphate groups or phosphate groups. Suitable alkanoyloxy groups are, for example, those derived from straight chained or branched, saturated aliphatic mono-carboxy 1 i c adds, for example: The formyloxy, acetoxy, propionoxy, butyroxy, pentanoyl oxy , hexanoyloxy, dimethyl acetoxy , trimethyl-acetoxy, diethyl acetoxy , tert . -butyl acetoxy , Furthermore , frh-e- -2-1 — y-Vi-c- -a-c-i-d- -ntoitoe-s-t-e-r-s-,- -a-r h -a-l-s-o-the sulphuric acid and phosphoric acid esters, may be converted into their alkali salts, for example, the sodium or potassium salts, in order to increase their solubility in water.

As a D-homo-steroi d of the general formula I in which Rg and/or Rg represent a lower alkyl group there is to be understood preferably a compound in which the alkyl groups Rg and Rg contain 1 to 4 carbon atoms. As alkyl groups R5 and Rg there may be mentioned, for example, the methyl group, the ethyl group, the propyl group and the butyl group.

The new D-homo-stero ds of the general formula I can be prepared in a manner in itself known by a process which is characterised 1n that, (a) hypochlorous acid, hypobromous acid, chlorine or fluorine and chlorine are additively combined at the A9^^-double bond of a compound of the general formula II GH2R1 in which X, -A-B- and R-j have the meanings given for formula I, and optionally the resulting 11 g-hy droxy-9a-hal ogen steroids are converted by treatment with bases into the corresponding 9 , 11 -epoxy-steroi ds , and then the epoxide ring is opened with hydrogen fluoride or hydrogen chloride or a bromine atom additively combined in the 9oposition is reductively el minated, or (b) a compound of the general formula III in which X, Y, Z, -A-B. and R^.'have the meanings given for formula I. and R-, represents a hydrogen atom or a lower acyl residue, is oxidized to the 4 corresponding 3-keto-A -steroid, optionally after hydrolysing the 3-acyloxy group, or (c) HV is split off from a compound of the general formula IV in which X, Y, Z, r formula I, and V represents a hydroxy 1 group or a bromine atom, or (d) for the preparation of D-homo-steroids of the general formula I in which Y represents a hydrogen atom, a compound of the general formula V in which X, -A-B^^. and R. have the meanings given for formula I is hydroxylated in the 11-position by 11 β-hydroxylating microorganisms, or (e) in a compound of the general formula VI in which r formula I, and W represents an alkylsulphonyloxy group, and arylsulpho nyloxy group, a bromine atom or an iodine atom, the substituent W is exchanged for a hydrogen atom, a fluorine atom, a chlorine atom, an acyloxy group or a phosphate residue, or (f) for preparing D-homo-steroids of the general formula I in which and R^ represents a hydroxyl group, additively combining hydroxy! groups at the ^-double bond of a compound of the general formula VII in which X, Y, Z and R. have the meanings given for formula I, or (g) for preparing 17-methyl-D-homo-steroids of the general formula I, a compound of the general formula VIII in which X, Y, Z and R. have the meanings given for formula I, and U represents an alkylene residue, preferably a branched chain alkylene residue, containing 3-10 carbon atoms, for example, the 2,2-dimethyl-propylene residue, or a phenyl ene residue, is reacted with a methyl magnesium halide or lithium copper dimethyl, optionally the 20-oxo group is converted by reaction with acyl chlorides or acyl bromides into the 20-enol-acylate, and the latter is epoxidised with peracids and the resulting reaction product is subsequently hydrolysed by treatment with acid, 4 and optionally the D-homo-Δ -steroids of the general formula I obtained by the process variants (a) to (g) are dehydrogenated in the 1-position and/or ester groups or ketal groups present are split off by hydrolysis and/or hydftoxyl groups present are esterified or condensed with carbonyl -compounds of the general formula R-.RgC0, in which R-. and Rg have the meanings given above.

By the process of the invention there can be prepared, for example, the following anti-inflammatoral ly active D- homo -steroids: 11 ,21 -di hydroxy-D-homo-4-pregnen-3 ,20-dione , 113,21 -di hydroxy- D-homo-1 ,4-pregnadi en-3 ,20-di one , 6a-f 1 uoro-11 ,21 -di hydroxy-17 -methyl -D-homo-4-pregnen-3 ,20-dione , 6 -f 1 uoro-113 ,21 -di hydroxy-17a-methyl -D-homo-1 ,4-pregnadien-3 ,20-di one , 9a- f 1 uoro-11 ,21 -di hydroxy-17a-methyl -D-homo-4-pregnen-3 ,20-di one , 9a-fl uoro-113,21 -di hydroxy-17a-methyl -D-homo-1 ,4-pregnadi en-3, 20-di one, 6a,9a-di f 1 uoro-11 β ,21 -di hydroxy-17a-methyl -D homo-4-pregnen-3 ,20-dione , 6a,9a-di f 1 uoro-11 ,21 -di hydroxy-17a-methyl -D-homo-1 ,4-pregnadien-3,20-dione, 6a-f 1 uoro-9a-chl oro-11 ,21 -di hydroxy-17a-methyl -D-homo-4-pregnen-3, 20-di one, 6a- f 1 uoro-9a-chl oro-11 ,21 -di hydroxy-17a-methyl -D-homo-1 ,4-pregnadien-3,20-dione, 6a, 113-di fl uoro-9a-chl oro-21 -hydroxy-17a-methyl -D-homo-1 ,4-pregnadi en-3 ,20-dione , 6a- f 1 uoro-9a,l 1 -di chl oro-21 -hydroxy-17a-methyl -D-homo-1 ,4-pregnadi en-3,20-dione, and also the 21-acetates , 21 -propionates , 21-butyrates, 21-valerates, 21-caproates and the sodium salts of 21 -mono-sulphate esters or 21 -monophosphate esters of these compounds, and also 113,17aa-21-trihydroxy-Ί 7a-methyl -D-homo-4-pregnen-3 ,20-dione , 113,17aa-21-trihydroxy-17a-methyl-D-homo-l ,4-pregnadien-3,20-dione, 6a-f 1 uoro-113,17aa,21 -tri hydroxy- 17a-methyl -D-homo-4-pregnen-3 ,20-di one , 6a-fluoro-ll 3,17aa, 21 -tri hydroxy-17a-methyl -D-homo-1 ,4-pregnadi en-3, 20-di one, 6 ,9a-di f 1 uoro-116,17aa,21 -tri hydroxy- 17 -methyl -D-homo-1 ,4-pregnadi en-3 ,20-di one, 6 -f 1 uoro-9a-chl oro-11 ,17a ,21 -tri hydroxy-1 ¾ -methyl -D-homo-1 ,4-pregnadien-3,20-dione, 6a-f 1 uoro-9 ,ll 3-di chl oro-17aa, 21 -di hydroxy-17a-methyl -D-homo-1 ,4-pregnadi en-3,20-dione, 9a- f 1 uoro-113,17a -521 -tri hydroxy-D-homo-4-pregnen-3 ,20-dione , 9a-fluoro-ll ,17aa,21-trihydroxy-D-homo-l ,4-pregnadien-3,20-dione and Vl-3r-l-7a^2 -¾-Hhydroxy-6a>17a-d4mGthyl 1,4 prcgnadicn-3,20-dionc and also the the-l7-a---aceta±es , 21-acetates, 1 a?21-d-iaGe-ta4:es-, 21-butyrates, 21-valerates, 21-caproates and the sodium salts of the 21-monosulphate esters or monophosphate esters of these compounds, and furthermore 113,17a, 17aa,21 -tetrahydroxy-D-homo-4-pregnen-3 ,20-dione , \fr, †?crcr,21— t-fH b 4r-oxy- l-Ta-a eet^y- D-» ofiio » -φ egne ^- 3 y one-, 113,21 -di hydroxy-17a, 17aa-isopropyli denedi oxy-D-homo-4-pregnen-3, 20-di one, 113,1 a,17aa,21-tetrahydroxy-D-h0mo-l ,4-pregnadi en-3, 20-di one, VH3-, * 7-ace-,€ -t +iy wxy- ITo^acetoxy- D uwio * V ^ p&gj¾ilien.--3,20.--£l-ioae 113 ,21 -di hydroxy-17 , 17aa-i sopropy 1 i denedi oxy-D-homo- 1 ,4-pregnadi en-3 , 20-di one , 6a- fl uoro-113,17a, 17aa, 21 -tetrahydroxy-D-homo-4-pregnen-3,20-dione, 6a- fl uoro-113 ,21 -di hydroxy- 17a , 17aa-i sopropy 1 i denedi oxy-D-homo-4-pregnen-3,20-dione, 6a-f 1 uoro-113 ,17a, 17aa,21-tetrahydroxy-D-homo-l ,4-pregnadien-3, 20-di one , 6 -f 1 uoro-113 ,21 -di hydroxy-17a ,17aa-i sopropyl i denedi oxy-D-homo-1 ,4-pregnadien-3,20-dione, 6a ,9a-di f 1 uoro-11 ,17a ,17a ,21 - tetr a hydroxy- D-homo-1 ,4-pregnadi en-3 ,20-di one , 6a ,9a-di f 1 uoro-113 ,21 -d1 hydroxy-17a ,17aa-i sopropyl -i denedi oxy-D-homo-1 ,4-pregnadi en-3 ,20-di one , 6a- f 1 uoro-9a-chl oro-113, 17a, 17aa ,21 -tetrahydroxy-D-homo-1 ,4-pregnadi en-3, 20-di one, 6a-fluoro-9a-chloro-ll3,21-di hydroxy-17 ,17aa-i sopropyl i denedi oxy-D-homo-1 ,4-pregnadi en-3, 20-di one, 6a- l uoro-9a ,113-d i chl oro-17a ,17aa ,21 -trihydroxy-D-homo-1 ,4-pregnadi en-3, 20-di one, 6a- 1 uoro-9a ,11 β - d i chl oro-17a ,17aa-i sopropyl i denedi oxy-D-homo-1 ,4-pregnadien-3,20-dione, 9a-fluoro-ll$,l 7a 7aa , 21 - te tra hydro xy-D- homo -4 -pregnen -3,20-dione, 9a-fl uoro-113 ,21 -d1 hydroxy-17a ,17aa-i sopropyl i denedi oxy-D- homo-4- pregnen- 3 ,20-di one , 9a-fl uoro-11 ,17a,l 7aa,21-te tra hydroxy -D- homo- 1 ,4-pregnadi en-3 ,20-di one and 9a-f.l uoro-113,21 - di hydroxy-17a ,17a a- i sopropyl i denedi oxy-D-homo-1 ,4-pn¾nadi en-3 ,20-di one and also the 21-acetates, 21 -butyrates , 21 -val erates , 21-caproates and the sodium salts of 21 -monosul phate esters or monophosphate esters of these compounds, and furthermore 6a-fluoro-ll3J7al7a tr1 hydroxy- D- homo- 1 ,4-pregnadi en-3,20-dione, 6a- f 1 uoro-11 β-hy droxy-17 ,17aa-i sopropyl i denedi oxy-D-homo-1 ,4- regnadi en-3 , 20-di one and 6a- f 1 uo'ro-11 β ,17aa-d1 hydroxy -17a-methyl -D-homo-1 ,4-pregnadien-3,20-dione.

It has already been stated that the new D-homo-sterolds of the general formula I can be prepared by methods in themselves known.

For the process according to variant (a) there are numerous possibilities to choose from. Thus, for example, chlorine itself or chlorine monofluoride may be additively combined at the A9^^-double bond. The additive combination of chlorine or fluorine and chlorine at the Δ9^11 double bond takes place especially well, if at the same time there is caused to react with the compounds containing a Δ^^-double bond an N-chloracyl amide, for example, N-chloracetamide or a N-chloracylimide, for example N-chlorosuccinimide and hydrogen chloride or hydrogen fluoride, or an alkali fluoride or alkali chloride, for example, lithium chloride or potassium hydrogen di fluoride.

The additive combination of hypochlorous acid or hypobromous acid at the Δ9^ ^-double bond of the compounds of the general formula II is also carried out by methods in themselves known, for example by reacting a compound of the general formula II in the presence of water and mineral acids, for example, sulphuric acid or perchloric acid, with an Njchlor-acyl amide, N-chloracylimide, N-bromacyl amide or N-bromacylimide (for example, N-chloracetamide, N-bromacetamide, N-chlorosuccinimide or N-bromosuccinimide) .

When it is desired to prepare the 9 -chloro- or fluoro-compounds of the general formula I according to the process variant (a), the 113-hydroxy-9a-homo-compounds, or, in the case oifs the 9 -fluoro compounds, also the 1 l3-hydroxy-9 -chloro-compounds of the general formula I, which have been prepared by the additive combination of hypobromous or hypochlorous acid with compounds of the general formula II, may be c onverted into the corresponding 893,113-epoxides by treatment with bases (for example, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium acetate or potassium acetate and pyridine), which epoxides are then converted by reaction with hydrogen fluoride or hydrogen chloride into the finally desired 9a-fluoro- or 9a-chloro-D-homo-steroids of the general formula I.

When it is desired according to process variant (a) to prepare compounds of the general formula I which are unsubstituted in the 9a-position, it is of advantage, first, as described above, to prepare from compounds of the general formula II the corresponding 113-hydroxy- 9a-bromo-compounds , and to split off the 9ot-bromine atom from the latter in a manner in itself known. This splitting may be carried out by means of methods that are customarily used for the reductive elimination of bromine from bromhydrins. There may be mentioned, for example, the elimination of bromine by means of tri phenyl tin hydride or tri-n-butyl tin hydride under the conditions usual for this purpose.

For carrying out the process according to process variant (b) there may be used either microbiological methods or purely chemical methods.

Thus, for example, compounds of the formula III, which contain as substi-tuents R-, hydrogen or a lower acyl residue containing 1 to 6 carbon atoms, may be fermented under the usual conditions with micro-organisms of the genus Flavobacterium (for example, Flavobacterium dehydrogenans, Flavobacterium buccal is or Flavobacterium fulvum), whereby the corresponding 4 3-keto-A -steroids of the general formula I saturated in the 1 -position are obtained. Under these conditions the acyloxy groups in the 3-position and optionally thethe 21 -position are hydrolysed during the reaction.

Instead of micro-organisms of the genus Flavobacterium there may be used for this microbiological oxidation other micro-organisms, for example strains of the genuses Micrococcus (for example Micrococcus dehydrogenans), Corynebacterium (for example, Corynebacterium mediolanum), orcardia or Fusarium (for example, ^Fusari urn solani), with the use of which, as is known, in addition to oxidation of the 3-hydroxyl group and 1 isomerisation of the Δ -double bond, Δ -dehydrogenation frequently also takes place.

For the microbiological oxidation according to process variant (b) there are suitable, preferably, those compounds of the general formula III, in which the substituent X represents a hydrogen atom.

When the oxidation according to process variant (b) is carried out by purely chemical methods, it is necessary in the usual manner to split off an acyl residue optionally present in the 3-position before the oxidation. It is also of advantage to protect by acylation hydroxyl groups optionally present in the 17a- and/or 21-position.

The chemical oxidation of compounds of the general formula III is also carried out by known methods, for example, there may be mentioned the Oppenauer oxidation of these compounds for instance with aluminium isopropylate or aluminium tert. -butyl ate in ketones, such as acetone or preferably cyclohexanone.

The method according to process variant (c) may also be carried out in a manner in itself known. Thus, for example, hydrogen bromide may be split off from compounds of the general formula IV by treatment. with bases (for example, tri ethyl amine, potassium carbonate, calcium carbonate, sodium acetate and lithium carbonate). Furthermore, they may be used for splitting off hydrogen bromide and especially water inorganic or organic acids, for example, formic acid, acetic acid, oxalic acid, hydrochloric acid, phosphoric acid and sulphuric acid. During this last-mentioned splitting an optionally present substituent X (fluorine or methyl) in the 3-position is i somen* sed.

For carrying out the method according to process variant (d) there is used the usual fermentation with llg-hydroxylating micro-organisms. As micro-organisms there may be used, for example, mould strains of the genuses Curvularia (for example, Curvularia lunata, Cunninghamella (for example Cunninghamella bainieri, Cunninghamella elegans, Cunninghamella echinolata and Cunninghamella blackesleana), Absidia (for example Absidia orchidis and Absidia ooerula), Helmintoscorium, Rhizoctonia (for example Rhizoctonia solani), Verticil lium (for example Verticil lium theobromae), Stachylidium (for example Stachylidium bicolor) , Pellicularia (for example Pellicularia filamentosa) or Col letotri chum (for example Col lectotri chum pi si ) .

Fermentation with these micro-organisms is carried out under the usual conditions. Duwing this reaction an acyl group in the 21-position is generally split off. Process variant (d) is preferably carried out with those compounds of the general formula V which contain in the 21-pesition a; hydroxyl group or an acyloxy group.

The method according to process variant (e) may be carried out under the same conditions as are customarily used for exchanging in an organic compound a bromine or iodine atom, an alkane-sulphonyl group (preferably a methane-sulphonyl group) or an aryl -sulphonyl group (preferably a para-toluene-sulphonic acid group) for hydrogen, fluorine, chlorine, an acyloxy group or a phosphate residue. Thus, for example", in compounds of the general formula VI in which W represents an iodine atom or a para-toluene sulphonic acid group, these substituents can be elimi-n nated, for example, by treatment with zinc dust, whereby the corresponding D-bomo-steroids of the general formula I unsubstituted in the 21 -position are obtained. Furthermore, the compounds of the general formula VI may be reacted in a polar solvent with an alkali halidc (preferably potassium ■hydregon difkiorido or lithium chloride) oy- an alkali acylate (for example, sodium acetate), whereby the corresponding 21 fluoro-, 21 -chloro- , or 21- acyloxy-compounds of the general formula I are obtained. For this reaction there are suitable as polar solvents preferably dipolar aprotic solvents, such as dimethyl formamide, dimethyl acetamide, hexamethyl -phosphoric acid tri amide or N-methyl -pyrrol done, to which may, if desired, be added a small amount of a protonic solvent, such as methanol, ethanol or water.

When the process variant (§) is carried out with the use of alkali acylates as reaction components, it is of advantage to use as solvent for the reaction the free carboxylic acid corresponding to the alkali acylate.

The 21 ■ bromo — or 21-iodo-compoundG of the general formula VI can also bo converted by reaction with silver fluoride or silver acylates (for oxamplo > silver acetate) into the corresponding 21 fluoro — or 21 -acyloxy- compounds-. The 21 -monophosphate esters of the general formula I can' be prepared, for example, by heating the corresponding iodo-compounds of the general formula VI with phosphoric acid in the presence of an organic ' - The method according to process variant (f) may be carried out under the same conditions as are customarily used for the conversion 1 c of Δ -steroids into 16,17-dihydroxy-steroids . There may be mentioned, for example, the reaction of compounds of the general formula VII with osmium tetroxide or with potassium permanganate.

The method according to process variant (g) is carried out under the same conditions as are customarily used for. the additive com- 1 g bi nation of methyl at a ^ -double bond of pregnan-20-one derivatives. Thus, for example, compounds of the formula VIII may be reacted with a methyl magnesium halide, preferably in the presence of copper- (I) chloride or with lithium copper dimethyl, and there are obtained, after the usual decomposition of the Grignard solution, for example, with mineral acids, D-homo-steroids of the general formula I containing a methyl group in the 17a-position and a hydrogen atom in the 17aa-position.

If, on the other hand, the Grignard solution is reacted with acyl halides (preferably acetyl chloride), the reaction mixture is epoxidised by treatment with per-acids and the reaction mixture is then decomposed with mineral acids there are obtained D-homo-steroids of the general formula I containing a methyl group in the 17 -position In working up the reaction mixtures, when this is carried out in an acid medium, the ketal group in the 3-position is split off and simultaneously the Δ -double bond present in the molecule is isomer! sed.

The optional subsequent dehydrogenation of Δ^-D-homo- be carried out either by microbiological methods or by purely chemical 4 methods. Thus, for example, the Δ -steroids are dehydrogenated in the 1-position under the usual conditions with bacterial cultures of the genus Bacillus (for example, Bacillus lentus or Bacillus sphaericus) or Artrobacter (for example Artrobacter simplex). On the other hand, it is also possible to carry out the Δ^-dehydrogenation by heating the Λ^-steroids with oxidizing agents customarily used for this reaction,' for example, selenium dioxide or 2,3-dichloro-5,6-dicyanobenzoquinone, in inert solvents.

The optional subsequent hydrolysis of acyloxy groups in the •l?rl-7-a--a-ni €P 21 -position is carried out by the usual methods, for example by reacting the esters in aqueous or alcoholic solutions or solvent mixtures in the presence of strong acids, for example, sulphuric acid, hydrochloric acid, para-toluene sul phonic acid or trifluoracetic acid, or by reacting the esters in aqueous or alcoholic solutions or solvent mixtures in the presence of alkali alcoholates, alkali hydroxides or alkali carbonates. if i^e- hydro tysts- TS- -car r ed- oat -urvde? -ro&l d -Goratftione-, -i-t- As --poss>We--feQ- -hydro-T-yse-fche- 4 ^a -i-l -d>acy*©xy-e-homo-sfee-rcHds -of- the -gener-a-1 fopmu-l-a- 1 -se-l-ectvve-ly-to- -ttoe ~y-^ dH) y-l-7c ^6 kxy-B OBie-s-t-e e:i- s-.- If desired, a ketal group in the 17,17a-position may be hydrolysed. For example, by treating these compounds with acids in water-containing solvents or water-containing solvent mixtures.

An optional subsequent esterif cation of free hydroxy! groups in the 17a- -a»d w 21 -position may also be carried out by methods in themselves known. Thus, for example, the hydroxy-steroids may be esteri- fied with acyl chlorides or acyl anhydrides in the presence of acids, for example, hydrochloric acid, para-toluene sul honic acid, trifluoracetic acid or in the presence of bases, such as potassium carbonate, pyridine, collidine or para-dimethyl ami nopyri dine. On the other hand, it is possible to esterify the hydroxy-cempounds with carboxylic acids in the pres•e0nce of trifluoracetic anhydride. If these esterifications are carried out under mild conditions, as is known, only the primary and secondary hydroxyl groups are esterified, and any tertiary hydroxyl groups that may be present are not reacted. If it is desired to esterify selectively only the 21 -hydroxyl group of 17,17a,21-trihydroxy-steroids , it is of advantage to carry out this reaction by reacting the trihydroxy-compounds with the corresponding acyl" anhydrides in the presence of lead acetate.

From the 21-hydroxy-compounds of the general formula I there can be prepared in a manner in itself known the alkali sulphates of 21-mono-sulphuric acid esters, for example, by reacting the 21-hydroxy-compounds with sulphur tri oxide in pyridine, and converting the resulting sulphuric acid esters by treatment with alkali bases into the. alkal salts.

If desired, a 17,17a-diol grouping optionally present in D-homo-steroids of the general formula I may be condensed with carbonyl -compounds of the general formula R^ gCO. This reaction is advantageously carried out by reacting the diols with an excess of the corresponding carbonyl compounds in the presence of strong acids, for example, hydrochloric acid or perchloric acid or para-toluenes'ul phonic acid and with the addition of water-removing agents, for example, enol -acetates or of orthoformic acid tri-alkyl esters.

As stated above, the new D-homo-steroids of the general formula I possess a good antiphlogistic activity and are distinguished by a favourable dissociation between desired inflammation-inhibiting activity and undesired thymolytic, catabolic and mineral-corticoidal side effects. Furthermore, these compounds have the property of being metabolised in the human body in a manner different from that of the structurally analogous known corticoids that have a 5-membered D-ring in the steroid framework.

The new D-homo-steroids in combination with the carriers usual in galenical pharmacy are well suited for the streatment, for example of (a) local: contact dermatitis, eczemas of a wide variety of types, neurodermatitis , erythrodermia, first degree burns, Pruritus vulvae et ani , Rosacea, Erythematodes curaneus, psoriasis, Lichem ruber planus et verrucosus; (b) oral : acute and chronic polyarthritis, neurodermatites , bronchial asthma, hay fever and the like.

The D-homo-steroids of the invention are also suitable for the treatment of allergic disorders of the respiratory tract, for example, rhinitis or bronchial asthma.

The medicinal specialities are made up in the usual manner by converting the active substances with suitable additives, carrier substances and taste correctives into the desired forms of application, such as tablets, dragees, capsules, solutions, salves, inhalant preparations etc..

For oral use there are suitable more especially tablets, dragees and capsules, which contain, for example, 0.1 to 50 mg of D-homo-steroid and 50 mg to 2 grams of a pharmacologically inactive carrier, for example, lactose, amy lose, talcum, gelatine, magnesium stearate and the like, and also the usual additives. For topical administration there are suitable powders, salves, aerosols and like preparations, which preferably contain 0.01 to 2% of D-homo-steroid.

The starting compounds of the general formula II to VIII for the process of the invention are prepared by methods generally known to those skilled in the art, andiillustrated by way of example with reference to typical members in the following Examples.

The following Examples serve for further illustration of the invention.

EXAMPLES I. Syntheses Example 1 (a) To 45 g of magnesium shavings in 1400 ml of absolute ether are added dropwise 130 ml of- methyl iodide. When the magnesium has dissolved, 2500 ml of absolute tetrahydrofurane are slowly added, and the mixture is distilled until the distillate has a boiling point of 55°C. The mixture is then cooled to 20°C, 7 grams of copper- (I) chloride and a solution of 100 g of 33-acetoxy-D-homo-5,17(17a)-dien-20-one in 1000 ml of absolute tetrahydrofurane are added, and the mixture is stirred for 40 minutes at 20°C.

The mixture is then cooled to 0°C, 230 ml of 2N4Sulphuric acid are added dropwise to the mixture and the whole is then extracted with ethyl acetate. The extract is washed with sodium thiosulphate solution and water, dried over sodium sulphate and concentrated in vacuo.

To the residue so obtained are added, while warming, 300 ml of pyridine and 150 ml of acetic anhydride, and the resulting solution is allowed to stand for 16 hours at room temperature. The mixture is then poured into ice-water, and the precipitated product is filtered off with suction and dissolved in methylene chloride. The methylene chlpride solution is washed with dilute sulphuric acid and water, concentrated in vacuo, and the residue is recrystallised from methylene chloride-ethyl acetate. There are obtained 75.6 g of 3e-acetoxy-17a-methyl-D-homo-5-pregnen-20-one melting at 212-213°C. (b) To 30 g of 3 -acetoxy-17a-methyl-D-homo-5-pregnen-2O-one are added 300 ml of glacial acetic acid, and the whole is heated to 40-45°C. There is then added dropwise to the mixture in the course of 10 minutes a solution of 7.9 ml of bromine in 60 ml of glacial acetic acid. The reaction mixture is allowed to cool, it is poured into ice-cold potassium acetate solution, the precipitated product is filtered off with suction, dissolved in ethyl acetate, the ethyl acetate phase is washed 0 with water, evaporated to dryness in vacuo at. a bath temperature of 40°Crp and 5,6,21-tribromo-3g-acetoxy-17a-methyl-D-homo-pregnan-20-one is obtained. as a crude produdt. (c) To the crude product so obtained are added 800 ml of acetone and 80 g of sodium iodide, and the whole is stirred in the dark for 16 hours at 20°C. An ice-cold solution of sodium thiosulphate is then added to the reaction mixture, the precipitated iodide is filtered off, dissolved in ethyl acetate, the ethyl acetate phase is washed. with water, and concentrated in vacuo. (d) The residue so obtained is dissolved in 420 ml of dimethyl formamide, 24 ml of glacial acetic acid and 42 ml of tri ethyl amine are added and the whole is stirred for 4.5 hours under nitrogen at 110°C. The reaction mixture is then allowed to cool to room temperature, poured into ice-cold sodium chloride solution, the precipitated product is filtered off, and dissolved in methylene chloride. The methylene chloride solution is washed with water, dried over sodium sulphate, concentrated in vacuo, and the residue is purified by chromatography over a column of silica gel. There are obtained 19.5 g of 33,21-diacetoxy-17a-methyl-D-homo-5-pgegnen-20-one, which, after recrystallisation from ether-pentane melts at 135.5-137.5°C. (e) 24.4 g of 3B,21-diacetoxy-17a-methyl-D-homo-5-pregnen-20-one are dissolved in 250 ml of methylene chloride, 250 ml of a methanol ic solution of 1% strength of potassium hydroxide are added, and the whole is heated under reflux for 25 minutes. 3 ml of glacial acetic acid are then added to the reaction mixture, it is concentrated in vacuo, the residue is, taken up in tetrahydrof urane , and the resulting solution is concentrated in vacuo. The residue is recrystallised from acetone, and 15.8 g of 3 S21-dihydroxy-17a-methyl-D-homo-5-pregnen-20-one melt4ng at 198-202°C are obtained. (f) To 11.7 g of 3e,21-dihydroxy-17a-methyl-D-homo-5-pregnen-20-one are added 150 ml of dimethyl formamide, 20 ml of acetic anhydride and 1.1 g of lead di acetate, and whole is stirred for 90 minutes at room temperature.

The mixture is then poured into an ice-cold solution of sodium chloride, the precipitated product is filtered off with suction, and dissolved in methylene chloride. The methylene chloride extract is washed with water, dried, and concentrated in vacuo. The product so obtained is recrystallised from methylene chloride-diisopropyl ether, and 11.6 g of 33~hydroxy-21-acetoxy-17 -methyl-D-homo-5-pregnen-20-one melting at 188.5 - 191 °C are obtained. (g) To 20.5 g of 3$-hydroxy-21-acetoxy-17a-methyl-D-homo-5-pregnen-20-one are added 500 ml of toluene and 20 ml of cyclohexanone, and the whole is heated at the boil until a few ml have distilled off. There is then added to the mixture a solution of 4.4 g of aluminium isopropylate in 50 ml of toluene, the mixture is heated for a further hour sufficiently strongly that some of the solvent is continually distilled off.

The reaction mixture is allowed to cool, it is diluted with ethyl acetate, the ethyl acetate phase is washed with lN-sulphuric acid and water, and concnetrated in vacuo. The residue is purified by chromatography over a column of silica gel, recrystallised from acetone-hexane, and 15.7 g of 21-acetoxy-17a-methyl-D-homo-4-pregnen-3,20-dione melting at 200.5 -202°C are obtained. (h) A 2-litre Erlenmeyer flask, which contains 500 ml of a nutrient . solution sterilized fof 30 minutes at 120°C in an autoclave and consisting of 1% of corn steep liquor, 1% of soya bean powder and 0.05% of soya bean oil, adjusted to a pH-value of 6.2, is inoculated with a lyophilic culture of Curvularia lunata (NRRL 2380) and agitated for 72 hours at 30°C on a rotary agitator. With this preculture is inoculated a 20-litre fermenter of stainless steel, which contains 15 1 of a medium sterilized at 121°C and 1.1 atmospheres gauge and consisting of 1% of corn; steep liquor, 0.5% of starch sugar and 0.005% of soya bean oil, adjusted to a pH-value of 6.2. With the addition of silicone SH as anti-foaming agent, germination was carried out for 24 hours at 29°C with aeration (10 1/min) at a pressure s) of 0.7 atmosphere- gauge, while stirring (220 revs./min.). 1 1 of the culture liquor is transferred under sterile conditions into 14 1 of a medium sterilized as above and consisting of 1% of corn steep liquor, 1.25% of soya bean powder and 0.005% of soya bean oil, and growth is carried out under the same conditions. After 6 hours a solution of 3 g of 21 -acetoxy-17a -methyl -D-homo-4-pregnen-3,20-di one in 150 ml of dimethyl -formamide is added. After a contact time of 23 hours, the contents of the fermenter are extracted by sti ring twice with 10 1 of methyl isobutyl ketone each time, andithe extract is evaporated in vacuo at a bath with hexane temperature of 50°C. The residue is washed several times/in order to remove the silicone oil, and recrystallised from ethyl acetate with the addition of A-carbon, whereby 608 mg of pure 11β ,21-dihydroxy-17a-methyl-D-homo-4-pregnen-3,20-dione melting at 200.3°C are obtained.

Example 2 A 2-litre Erlenmeyer flask, which' contains 500 ml of a nutrient solution sterilized for 30 minutes at 120°C in an autoclave and consisting of 1,5% of peptone, 1.2% of corn steep and 0.2% of gSO^, adjusted to a pH-value of 6.5, is inoculated with a lyophilic culture of Bacillus lenthus (ATCC 13 805), and agitated for 24 hours at 30°C. With this preculture is then inoculated a 20-litre fermenter of stainless steel, which contains 15 1 of a liquid nutrient medium sterilized at 121°C and 1.1 atmospheres gauge and consisting of 0.2% of yeast extract, 1% of corn steep liquor and 0.1% of starch sugar, adjusted to a pH-value of 7.0. With the addition of silicone SH as anti-foaming agent germination is carried out at 29°C while aerating and stirring. After a growth phase of 6 hours, a solution of 3 g of ll3,21-dihydrpxy-17a-methyl-D-homo-4-pregnen-3,20-dione in 150 ml of dimethyl formamide is added.

After a contact time of 15 hours, the contents of the fermenter are extracted twice with 10 1 of methyl isobutyl ketone each time, and the extract is evaporated in vacuo. The residue was washed with hexane in order to remove the silicone oil, and recrystallised from acetone/d isopropyl ether in the presence of A-carbon, and 2.2 g of 113,21 -di hydroxy- 17a-methyl-D-homo-1 ,4-pregnadien-3,20-dione melting at 159°C. are obtained..

Example 3 To 200 mg of 113,21-dihydroxy-17a-methyl-D-homo-l ,4-pregnadien-3,20-dione are added 3 ml of pyridine and 0.3 ml of butyric anhydride, and the whole is heated under reflux for 15 minutes. The mixture is then allowed to cool, diluted with cyclohexane, and concentrated in vacuo.

The oily residue is triturated with pentane, the pentane solution is decanted off, the crude product so obtained is recrystallised. from methylene chloride-diisopropyl ether, and 140 ml of ll -hydroxy-21-butyroxy-17a-methyl-D-homo-1 ,4-pregnadien-3,20-dione melting at 156-158°C are obtained.

Example 4 To 5.0 g of ll3,21-dihydroxy-17a-methyl-D-homo-l ,4-pregnadien-3,20-dione are added 20 ml of pyridine and 10 ml of acetic anhydride, and the whole is kept at room temperature for 60 minutes. The reaction mixture is then poured into ice-water, the precipitated product is filtered off wiifi suction, dissolved in methylene chloride, the methylene chloride phase is washed with 2N-sulphuric acid and water, and concentrated in vacuo.

The residue is recrystallised from methylene chloride-diisopropyl ether, and 5.1 g of 11 -hydroxy-21-acetoxy-17a-methyl-D-homo-l ,4-pregnadien-3,20-dione melting at 170-172°C are obtained.

Example 5 (a) 50 g of ll3-hydroxy-21-acetoxy-17a-methyl-D-homo-l ,4-pregnadien-3,20-dione are dissolved in 44 ml of pyridine, and 22 ml of methane sul phonic acid chloride are added dropwise while stirring. The reaction mixture is heated at 80°C for 90 minutes, then allowed to cool, and poured into ice-water. The precipitated product is filtered off with suction, washed with water, dried n vacuo, recrystallised from methylene chloride-diisopropyl ether, and 39.2 g of 21-acetoxy-17a-ethyl-D-homo-1 ,4,9(11 )-pregnatrien-3,20-dione melting at 161 - 163°C are obtained. (b) 11 g of 21 -acetoxy-17a-methyl -D-homo-1 ,4,9(11 )-pregnatrien-3, 20-dione are suspended in 200 ml of tetrahydrofurane and 88 ml of IN-per-chloric acid are added. There are then introduced into the reaction solution, while stirring, 14..3 g of N-bromo-succinimide, and the whole is stirred for 30 minutes at 30°C. The mixture is poured into ice-cold sodium sulphite solution, the precipitated product is filtered foff with suction, taken up in methylene chloride, the methylene chloride phase is washed with water, concentrated in vacuo, and there is obtained 9a-bromo-113-hydroxy-21 -acetoxy-17a-methyl -D-homo-1 ,4-pregnadien-3 ,20-dione as a crude product. (c) To 13.6 g of the bromhydrin so obtained are added 22 g of potassium acetate and 100 ml of ethanol, and the whole is heated under reflux for 2 hours. The reaction mixture is then poured into water, the precipitated product is filtered off, dried in vacuo, and 93,113-epoxy-21-acetoxy-lofo-methyl -D-homo-1 ,4-pregnadien-3,20-dione is obtained as a crude product. (d) 8.0 g of the crude product so obtained are introduced into a mixture, cooled to -10°C, of 24 ml of dimethyl formamide and 24 ml of hydrogen fluoride, and the mixture is stirred for 10 hours at room temperature. The mixture is then poured into ice-water containing ammonia, the precipitated product is filtered off with suction, dissolved in methylene chloride, the methylene chloride phase is washed with water, and concentrated in vacuo. The residue is recrystallised from acetone-hexane, and 5.8 g of 9a-f luoro-113-hydroxy-21 -acetoxy-17a-methyl-D-homo- 1 ,4-pregnadien-3,20-dione melting at 183-185°C are obtained.

Example 6 To 3 g of 9a-fluoro-ll$-hydroxy-21-acetoxy-17a-methyl-D-homo-1 ,4-pregnadien-3,20-dione are added 12 ml of methanol and 12 ml of methylene chloride, the whole is cooled to -5°C, and a solution of 0.18 g of potassium hydroxide in 6 ml of methanol is added dropwise. The mixture is then stirred for a further 60 minutes at 0°C, neutralised with acetic acid, diluted with methyl enecchlor de, the methylene chloride phase is washed with water, concentrated in vacuo, and the residue is recrystall ised from methanol. 2.4 g of 9a-fluoro-llg,21-dihydroxy-17a-methyl-D-homo-l ,4-pregnadien-3,20-dione melting at 223 - 225°C are obtained.

Example 7 4 ml of pyridine are cooled to -15°C, and 0.26 ml of freshely distilled sulphur tri oxide is added, while stirring, in such a way that the internal temperature of the mixture does not exceed +5°C. Into the solution so obtained are introduced 2 g of 9a-fluoro-ll$,21-dihydroxy-17a-methyl-D-homo-1 ,4-pregnadien-3,20-dione, and the mixture is stirred for 30 minutes at 20°C, 40 ml of water are added, and the whole is stirred for a further 30 minutes. There aee then added to the reaction mixture 7 ml of a a IN-solution of sodium hydroxide until ttre- pH-value of 8.5 is reached. The mixture is extracted with methylene chloride, and the aqueous phase, after hydroxide adjusting the pH-value to 8.5 with an IN-solution of sodium drVoriie, ia concentrated in vacuo. The residue is dissolved in 50 ml of methanol, filtered, the filtrate is concentrated in vacuo, and the residue is dried in vacuo. There are obtained 1.8 g of sodium [9a-fluoro-l l -hydroxy-3,20-dioxo-17a-methyl-D-homo-l ,4-pe§gnadien-21-yl ] sulphate decomposing at 191°C.

Example 8 (a) A Grignard solution (prepared from 21 g of magnesium shavings and 72.5 g of methyl iodide and 1000 ml of ether) is diluted with 1000 ml of absolute tetrahydrofurane, and the mixture is distilled until the distillate ■J cooled to 20°C, g of copper(I) chloride and a solution of 50 g of 33-hydroxy-D-homo-5,17(17a)-pregnadien-20-one in 2000 ml of absolute tetrahydrofurane are added, and the mixture is stirred for 20 minutes at room temperature. The reaction mixture is then worked up in the usual manner, the crude product is recicystallised from acetone, and 32.5 g of 33-hydroxy-17a-methyl-D-homo-5-pregnen-20-one melting at 207-209°C are obtained. (b) 10 g of 3g-hydroxy-17a-methyl-D-homo-5-pregnen-20-one are suspended in 1000 ml of tetrahydrofurane, and a solution of 3.6 ml of bromine in 10 ml of glacial acetic acid is added dropwise (duration about 15 minutes). The reaction product is then worked up as described in Example lb_, and 33-hydroxy-5,6,21-tribromo-17a-methyl-D-homo-pregnan-20-one is obtained as a crude product. (c) The tribromo-deri vative so obtained is reacted under the conditions described in Example l with 300 ml of acetone and 35 g of sodium iodide and worked up, and the 21 -iodide compound is obtained as a crude product. (d) The 21 -iodide is dissolved in 140 ml of dimethyl formamide, 8 ml of glacial acetic acid and 14 ml of tri ethyl amine are added and the whole is stirred for 11 hours at 90°C. The reaction mixture is worked up as described in Example ld_, and 4.4 g of 33-hydroxy-21-acetoxy-17a-methyl-D-homo-5-pregnen-20-one are obtained, which, after recrystallisatton from methylene chloride/diisopropyl ether melts at 188 - 190°C. (e) Into a solution cooled to -30°C of 3 ml of hydrogen fluoride and 3 ml of dimethyl formamide are introduced 470 trig of N-bromosuccinimide. There is then added to the mixture in portions a precooled solution of 1 g of 33-hydroxy-21-acetoxy-17a-methyl-D-homo-5-pregnen-20-one in 8 ml of methylene chloride, the mixture is stirred for 10 minutes at -30°C, it is poured into an ice-cold solution of potassium hdyrogen carbonate, and extracted with methylene chloride. The methylene chloride phase is recrystallised from acetone, and 627 mg of 63-fluoro-5a-bromo-33-hydroxy-21-acetoxy-17a-methyl-D-homo-5a-pregnan-20-one melting at 168.5°C (with decomposition) are obtained. (f) To 300 mg of 63-fluoro-5a-bromo-33-hydroxy-21-acetoxy-17a-methyl-D-homo-5a-pregnan-20-o e in 10 ml of acetone is added dropwise 0.19 ml of Jones reagent (containing per litre 267 g of chromium(VI) oxide, 230 ml of concentrated sulphuric acid in water), and the mixture is stirred for minutes at 20°C. The mixture is then poured into ice-water, the precipitated product is filtered off with suction, taken up in methylene chloride, the methylene chloride phase is washed with water, and concentrated in vacuo. 298 mg of 63-fluoro-5a-bromo-21-acetoxy-17a-methyl-D-homo-5 -pregnan-3,20-dione are obtained as a crude product. (g) This crude product is dissolved in 5 ml of glacial acetic acid, and stirred foB 3 hours at 30°C. There are then added to the mixture 100 mg of sodium acetate, the whole is stirred for 10. minutes at 30°C, it is poured into ice-water, the precipitated product is filtered off with suction, and taken up in methylene chloride. The methylene chloride phase is washed with water, concentrated in vacuo, the residue is re-crystallised from acetone, and 250 mg of 6a-fluoro-21-acetoxy-17ct-methyl-D-homo-4-pregnen-3,20-dione are obtained. (h) Under the conditions described in Example lh^ 3 g of 6 -fluoro-21-acetoxy-17a-methyl-D-homo-4-pregnen-3,20-dione are fermented with Curvularia lunata, worked up, and 6 -f luoro-113,21 -dihydroxy-17a-methyl-D§homo-4-pregnen-3,20-dione is obtained.

Example 9 Under the conditions described in Example 2 1,1 g of66a-fluoro-ll3,21-dihyroxy-17a-methyl-D-hom8-4-pregnen-3,20-dione are reacted with a culture of Bacillus lentus, worked up, and there is obtained 6 -fluoro-113,21 -di hydroxy- 17a-methyl -D-homo-1 ,4-pregnadi en-3 ,20-di one .

) Example 10 To 10 g of 6 afluoro-ll$ ,21 -dihydroxy-17 -methyl -D-homo-1 ,4-pregnadien-3,20-dione in 40 ml of pyridine are added 20 ml of acetic anhydride, and the whole is stirred for 90 minutes at room temperature.

The reaction mixture is worked up as described in Example 3, and 9.5 g of 6a-fluoro-ll 8-hydroxy-21-acetoxy-17 a-methyl -D-homo-1 ,4-pregnadien-3,20-dione melting at 213-215°C are obtained.

Example 11 (a) To 5 g of 6 -fluoro-ll 3,21-dihydroxy-17a-methyl-D1;j mo-l ,4-pregnadien-3,20-dione are added 15 ml of pyirtddine and 5 ml of trimethyl acetic anhydride, and the whole is heated under reflux for 6 hours. The reaction mixture is diluted with 30 ml of pyridine, cooled to +5°C, 2 ml of thionyl chloride are added dropwise to the solution, and the mixture is stirred for 30 minutes at 0°C. The mixture is then poured into ice-water, the precipitated product is filtered off with suction, washed with water, dried in vacuo, recrystallised; a'from methylene chloride, and 4.9 g of 6a-fluoro-21 -trimethyl acetoxy-17a-methyl -D-homo-1 ,4,9(11 )-pregnatrien-3,20-dione melting at 191-192.5°C are obtained. (b) 380 mg of 6a-fluoro-21 -trimethyl acetoxy-17a-methyl -D-homo-1 ,4,9(11 )-pregnatrien-3,20-dione are. dissolved in 15 ml of tetrahydrofurane, and 1 ,2 g of N-chlorosuccinimide and 11 ml of IN-aqueous perchloric acid are added. The mixture is then stirred for 3 hours at 35°C, it is poured into ice-water, extracted with methylene chloride, the methylene chloride phase is washed with water, and concentrated in vacuo. The residue is recrystal-lised from acetone-diisopropyl ether, and 250 mg of 6a-fluoro-9a-chloro-llg-hydroxy-21 -trimethyl acetoxy-17a-methyl -D-homo-1 ,4-pregnadien-3,20-dione melting at 221-223°C are obtained.

' Example 12 (a) To 500 mg of 6 -fluoro-ll 3-hydroxy-21-a,cetoxy-17a-methyl-D-homo-l ,4-pregnadien-3,20-dione are added 25 ml of dimethyl formamide, 4.5 ml of pyridine and 2.2 ml of methane sulphonic acid chloride, and the whole is heated for 90 minutes at 80°C. The reaction mixture is worked up as described in Example 5a, and 402< mg of 6a-fluoro-21-acetoxy-173-methyl-D-homo-T,4,9(ll )-pregnatrien-3,20-dione melting at 187-189°C are obtained. (b) 375 mg of 6 -fluoro-21-acetoxy-17ot-methyl-D-ii0mo-l ,4,9(11 )-pregnatrien-3,20-dionee are dissolved in 15 ml of tetrahydrofuran, 1.2 g of N-chloro-succinimide and 11 ml of IN-aqueous perchloric acid are added, and the whole is stirred for 3 hours at 35°C. The reaction mixture is worked up as described in Example lib, and 266 mg of 6x -fl uoro-9o-chloro-113-hydroxy-21-acetoxy-17a-methyl-D-homo-1 ,4-pregnadien-3,20-dione melting at 207-209°C are obtained.

Example 13 (a) 5.0 g of 6 -fluoro-113-hydroxy-21-acetoxy-17a-methyl-D-homo-l ,4-pregnadien-3,20-dione are reacted and worked up under the conditions described in Example 5a, and 3,7 g of 6a-fluoro-21-acetoxy-17a-methyl-D-homo-l ,4,9(11 )-pregnatrien-3,20-dione melting at 173-175°C are obtained. (b) The'pregnatrien compound so obtained is converted under the conditions described in Example 5b-d into 6a,9ord fluoro-ll 3-hydroxy-21-acetoxy-17^-methyl-D-homo-1 ,4-pregnadien-3,20-dione meltingaat 199-2 i°C.

Example 14 3.0 g of 6 ,9 -difluoro-llg-hydroxy-21-acetoxy-17 -methyl-D-homo-l ,4-pregnadien-3,20-dione are hydrolysed under the conditions described in Example 6, and 2.6 g of ea^a-difluorollS ,21-dihydroxy-17a-methyl-D-homo-l ,4-pregnadien-3,20-dione melting at 190-191°C are obtained.

Example 15 1.0 g of 6 -fluoro-21-acetoxy-17a-methyl-D-homo-l ,4,9(11 )-pregnatrien-3,20-dione is dissolved in 50 ml of glacial acetic acid, 4 g of lithium chloride 1 ml of tetrahydrofuran, and the mixture is heated for 5 hours at room temperature and poured into ice-water. The precipitated product is filtered off with suction, taken up in methylene chloride, the methylene chloride phase is washed with water, concentrated in vacuo, the residue is recrystal-lised from ether-pentane , and 590 mg of 6a-fluoro-9a,ll -dichloro-21-acetoxy-17a-methyl-D-homo-l ,4-pregnadien-3,20dione melting at 232-234°C are obtained.

Example 16 A mixture of 4.2 ml of hydrogen fluoride, 5.7 ml of tetrahydrofuran and 8 ml of methylene chloride is cooled to -70°C, 2.0 g of 6a-fluoro-21-acetoxy-17 -methyl-l ,4,9(11 )-pregnatrien-3,20-dione and 1.0 g of N-chlorosuccinimide are added, and the mixture is stirred for 5 hours then at -60°C. A further 2.0 g of N-chlorosuccinimide are/added to the mixture, and the whole is allowed to stand for 15 hours at 0°C. The reaction mixture is introduced into an ice-cold solution of potassium hydrogen carbonate, extracted with methylene chloride, the methylene chloride phase is washed with sodium sulphate solution and water, and concentrated in vacuo. The residue is recrystallised from acetone-hexane, and 1.3 g of 6a, 113- I di fl uoro-9a-chl oro-21 -acetoxy-l^a-methyl -D-homo-1 ,4-pregnadien-3 ,20-dione melting at 244 -246°C are obtained.

Example 17 Into a solution of 20 g of 6a-fluoro-ll$,21-dihydroxy-17a-methyl -D-homo-1 ,4-pregnadien-3,20-dione in 200 ml of pyridine are added dropwise, while cooling and stirring, 20 ml of methane sulphonic acid chloride. After a reaction period of 30 minutes, the reaction solution is poured into ice-water, and the precipitated 21 -mesylate is filtered off. 15.4 g of the 6a-f luoro-ll3-hydroxy-21-mesyloxy-17a-methyl -D-homo-1 , 4-pregnadien-3,20-dione so obtained are dissolved in 500 ml of acetone, and, after the addition of 15.4 g of sodium iodide in 400 ml of acetone, the mixture is heated for 15 minutes at the boil. The filtered reaction solution V. ϋ is evaporated in vacuo. The residue is stirred (j/ith a dilute solution of sodium thiosulphate, filtered off with suction, washed with water, dissolved in 300 ml of acetone, and precipitated in the warm with 120 ml of water.

After cooling, there are isolated 14.1 g of 6a-fluoro-21-diodo-llg-hydroxy-17a-methyl-D-homo-l ,4-pregnadien-3,20-dione, 14.1 g of the 21- iodo-compound are dissolved in 700 ml of acetonitrile, and heated under reflux for 3 hours with 14.1 ml of orthophosphoric acid and 42 ml of tri-ethylamine. The reaction solution is then concentrated under reduced pressure, the residue is taken up inmmethanol , and the solution is ^adjusted to a pH- value of 11 with a ΐΝ-methanolic solution of sodium hydroxide. The residue is filtered off, the filtrate is evaporated in vacuo, and the residue is taken up in 70 ml of methanol. By the addition of ether the disodium salt is precipitated. The disodium salt can be purified by repre-r cipitation from methanol with ether. 11.9 g of disodium (6a-fluoro-l 13-,hydroxy-3,20-dioxo-17a-methyl-D-homo-l ,4-pregnadien-21-yl )-phosphate are obtained.

Example 18 Under the conditions described in Examples 8e, f and 9 there is obtained from 33-hydroxy-21-acetoxy-D-homo-5-pregnen-20-one 6 -fluoro-21-acetoxy-D-homo-4-pregnen-3,20-dione melting at 178 -180°C, which can be converted under the conditions described in Example lh into 6a-fluoro-1 lg,21-dihydroxy-D-homo-4-pregnen-3,20-dione.

Example 19 (a) An Erlenmeyer flask containing 500 ml of sterilized aqueous medium containing 0.3% of yeast extract, 0.5% of corn steep liquor and 0.2% of starch, adjusted to a pH-value of 7, is inoculated with a lypphilic culture of Flavobacterifurh dehydrogenans (ATCC 13930), and is agitated for 48 hours at 30°C and 145 revolutions per minute. A 20-litre fermenter, charged with 14.75 1 of a sterilized nutrient solution of the same composition is inoculated with 250 ml of the above bacterial suspension, and the mixture is stirred for 24 hours at 29°C with aeration at a rate of 1650 1/h and at 220 revolutions per minute. 0.9 1 of this prefermentation is transferred into a 20-l tre fermenter, which is charged with 15 1 of sterilized medium of the same composition. For the main fermentation there are used the same conditions' as those of the prefermentation. During the main fermentation the pH-value is maintained between 6 and 7. After a growth phase of 6 hours, 3.0 g of 3$,21-diacetoxy-17a-methyl-D-homo-5-pregnen-20-one in 60 ml of dimethyl-formamide are added and fermented.

After a reaction period of 32 hours the fermentation mixture is extracted twice with 15 1 of methyl isobutyl ketone each time,. the organic phase is concentrated, the residue is taken up in methylene chloride, the methylene chloride phase isipfiltered over silica gel, and concentrated in vacuo. 2.7 g of 21-hydroxy-17a-methyl-D-homo-4-pregnen-3,20-dione are obtained as a crude product. (b) Without further purification the 21-hydroxy-17a-methyl-D-homo- 4-pregnen-3,20-dione so obtained is fermented under the conditions described in Example lh with Curvularia lunata, and, after the usual working up, there are obtained 480 mg of ll ,21-dihydroxy-17a-methyl-D-homo-4-pregnen-3,20-dione melting at 198-199.5°C.

Example 20 (a) Under the conditions described in Example lh 3.0 g of 6a-fluoro-21-acetoxy-17a-methyl-D-homo-4-pregnen-3,20-dione are fermented with Aspergillus occhraceus (ATTC 1008). When the fermentation has terminated, the fermentation batch is extracted with methyl isobutyl ketone, the methyl isobutyl ketone extract is concentrated in vacuo , and 6a-fluoro-na,21-dihydroxy-17a-methyl-D-homo-4-pregnen-3,20-dione is obtained as a crude product. - - ϋ (b) The crude product so obtained is fermented under the conditions described in Example 2 with Bacillus lentus. The reaction mixture is worked up in the usual manner, and 890 mg of 6a-fluoro-lla,21- dihydroxy-17a-methyl-D-homo-l ,4-pregnadien-3,20-dione are obtained. (c) To 750 mg of 6a-fluoro-lla,21-dihydroxy-17a-methyl-D-homo- 1 ,4-pregnadien-3,20-dione in 10 ml of dimethyl formamide are added 2 ml of acetic anhydride and 0.2 g of lead di acetate, and the whole is stirred for 60 minutes at room temperature.

The reaction mixture is diluted with methylene chloride, the methylene chloride phase is washed with water and concentrated to dryness. (d) the resulting crude product of 6a-fluoro-lla-hydroxy-21- acetoxy-17 -methyl-D-homo-l ,4-pregnadien-3,20-dione is maintained for 3 hours at 0°C with 7 ml which is then extracted with chloride. The reaction methylene chloride phase is concentrated in vacuo.

The residue so obtained is dissolved in 10 ml of dimethyl - formamide, 0¾ g of lithium chloride is added, and the mixture is heated for 90 minutes at 100°C.

The mixture is then poured into ice-water, extracted with methylene chloride, the methylene chloride phase is washed with water, and concentrated in vacuo. The crude product so obtained is purified by chromatography over a column of silica gel, recrystallised from methylene chloride-diisopropyl ether, and 210 mg of 6a-fluoro-21-acetoxy-17a- methyl-D-homo-1 ,4,9(11 )-pregnatrien-3,20-dione melting at 186-188°C are obtained. (e) 200 mg of 6a-fluoro-21-acetoxy-17a-methyl-D-homo-l ,4,9(11 )- pregnatrien-3,20-dione are reacted with N-bromo-succinimide under the conditions described in Example 5b, and 180 mg of 6a-fluoro-9a-bromo-113- hydroxy-21-acetoxy-17a-methyl-D-homo-l ,4-pregnadien-3,20-dione are obtained as a crude product. 0 (f) The bromhydrin so obtained is dissolved in 4 ml of tetrahydrofurane, 1.2 ml of tributyl tin hydride are, added, and the whole is heated for 90 then minutes at 80°C. 1 mg of azo-diisobutyronitrile is/ added to the mixture, and the latter is heated for a further 30 minutes.

The reaction mixture is then poured into ice-water, extracted with methylene chloride phase is washed with lN-sulphuric acid, sodium hydrogen carbonate solution and water, concentrated in vacuo, and 110 mg of 6a-fluoro-ll¾-hydroxy-21-acetoxy-17a-methyl-D-homo-4-pregnen-3,20-dione are obtained.

Example 21 (a) To 5.6 g of 3$-acetoxy-D-homO-5,17-pregnadien-20-one are added 350 ml of tetrahydrofuran and 6.8 g of copper(II) bromide, and the whole is heated for 4 hours under reflux. The mixture is then poured into ice-water .extracted with methylene chloride, the methylene chloride phase is washed, concentrated in vacuo, and 21-bromo-3g-acetoxy-D-homo-5,17-pregna-dien-20-one is obtained as a crude product, which, after recrystallisation from ether-hexane, melts at 155-157°C. (b) The bromide is reacted under the conditions described in Example Id, and there is obtained, after the usual working up, 3$,21-diacetoxy-D-hom r5,17-pregnadien-20-one (melting at 133-134°C). (c) The diacetate so obtained is hydrolysed under the conditions described in Example le, and 33,21-dihydroxy-D-homo-5,17-pregnadien-20-one is obtained. (d) The dihydroxy-compound is esterified under the conditions described in Example If, and 33-hydroxy-21-acetoxy-D-homo-5,17-pregnadien-20-one melting at 201-202°C is obtained. (e) To a solution of 5.7 g of 3g-hydroxy-21-acetoxy-D-homo-5,17-pregnadien-20-one are added 170 ml of toluene, 80 ml of cyclohexanone and 6.6 g of alumi ium tert. -butyl ate, and the whole is heated for 2 hours under α reflux under a water separator. The mixture is then poured into ice-water, acidified with hydrochloric acid, and extracted with emethylene chloride. The methylene chloride phase is washed with water, dried over sodium sulphate, concentrated in vacuo, and the residue is purified by chromatography over a column of silica gel. 21-Acetoxy-D-homo-4,17-pregnadien-3,20-dione melting at 159-160°C is obtained. (f) 3.0 g of 21-acetoxy-D-homo-4,17-pregnadien-3,20-dione are dissolved in 300 ml of benzene and 30 ml of pyridine, and a solution of 2. g of osmium tetroxide in 60 ml of benzene is added. The mixture is stirred for 2 hours at room temperature, concentrated in vacuo, the residue is dissolved in 400 ml of dioxane, 80 ml of (ajsolution of 40% strength of sodium hydrogen sulphute are added and the mixture is stirred for a further 30 minutes. The mixture is then concentrated in vacuo to one half of its volume, the residue is poured into ice-water, extracted with oethylene chloride, the methylene chloride phase is washed with sodium carbonate solution and water, dried over sodium sulphate, and evaporated in vacuo. The residue is purified over a column of silica gel, and 17 ,17aa-dihydroxy-21-acetoxy-D-homo-4-pregnen-3,20-dione melting at 230-232°C (from acetone) is obtained. (g) The 17a>17aa-dihydri»xi'J-21-acetoxy-D-homo-4-pregnen-3,20-dione is fermented under the conditions described in Example Ih with Curvularia lunata, and there is obtained, after the usual working up, ll3,17a»17aa,21-tetrahydroxy-D-homo-4-pregnen-3,20-dione melting at 261-262°C.

Example 22 (a) 33,ll3-Diacetoxy-androsta-3,5-dien-17-one in methylene chloride is ^reacted with ethylene glycol in the presence of orthoformic acid methyl ester and para-toluene sulphonic acid at room temperature to form 3,11 -diacetoxy-17,17-ethylene-^i¾xy-androsta-3,5-diene (melting at 18'3-186°C).

This 17-ketal is reduced in tetrahydrofurane-methanol with sodium borohydride to form ll3-acetoxy-17,17-ethylene-dioxy-33-hydroxy-androst-5-ene (melting at 125-126°C).

The ketal is split in aqueous acetone with para^toluene sulphonic acid to yield ilT3-acetoxy-33-hydroxy-androst-5-en-17-one (melting at 193-195°C).

This 17-keto-steroid is reacted with dimethyl -sulphoxoni urn methylide in dimethyl formamide to form 21-nor-ll 3-acetoxy-17,20-epoxy-33-hydroxy-pregn-5-ene (melting at 155-156°C).

The epoxide is reacted in alcohol and concentrated ammonia in an autoclave to form ll3-acetoxy-17-aminomethyl-3g,17a-dihydroxy-androst-5-ene. With sodium nitrite in glacial acetic acid and water there is obtained therefrom D-homo=ll 3-acetoxy-33-hydroxy-androst-5-en-17a-one melting at 230-232°C.

Hydrolysis of the Il3-acet2te in a boiling methanol ic solution of potassium hydroxide yields D-homo-33,113-dihydroxy-androst-5-en-17a-one melting at 234-236°C. 33,11 -Dihydroxy-D-homo-androst-5-en-17a-one is condensed with oxalic acid diethyl ester to form 33,113-di hydroxy-17-ethoxalyl-D-homo-androst-5-en-17a-one.

The latter is reacted with methyl iodide in acetone in the presence of potassium carbonate to form the 17-methyl derivative.

By splitting off the oxalyl residue in a methanol ic solution of sodium methylate there is obtained 33,ll3-dihydroxy-17a-methyl-D-homo-androst-5-en-17a-one melting at 209-211 °C. ; The 33,ll3-dihydroxy-17a-methyl-D-homo-5-androsten-17a-one is reacted in tetrahydrofurane with ethinyl magnesium bromide, and there is obtained 33,113,17aa-tri hydroxy-17a-methyl -17a -ethi nyl -D-homo-5-androstene , which after treatment with mercury para- toluene sulphonic acid amide in boiling alcohol yields 33 ,11 ,17aa-tri hydroxy-17a-methyl-D-homo-5-pregnen-20-one melting at 212-214°C. (b) To 1.7 g of 33, 113,17a -tri hydroxy-17a-methyl-D-homo-pregn-5-en-20-one in 10 ml of methanol are added 2.1 ml of a methanol ic solution of 10% strength of calcium chloride and 1 g of calcined calcium oxide. \ j A solution of 2.32 g of iodine and 600 mg of calcium chloride in 6 ml of" * then methanol is /added dropwise in the course of 30 minutes, while continuously stirring. Stirring is continued for a further 10 minutes, the mixture is poured into ice-water and extracted with methylene chloride. The extracts are washed with dilute sodium dthloride solution, dried and evaporated.

There are obtained 2.5 g of thin layer chromatographically unitary 3 ,ll ,17a trihydroxy-21-21-diiodo-17 -methyl-D-homo-pregn-5-en-20-one, which is further worked up without purification. (c) 2.5 g of the above described di iodide in 30 ml of acetone are boiled under reflux for 5 days with 0.3 ml of water, 0.3 ml of acetic acid and 3 g of potassium acetate. The mixture is poured into water, and extracted with methylene chloride. The methylene chloride solutions are washed with dilute sodium chloride solution, dried and evaporated. There are obtained 1.9 g of thin layer chromatographically almost unitary 33',ll3,17aa-trihydroxy-21-acetoxy-17a-methy 1 -D-homo-pregn-5-en-20-one . (d) . The latter is reacted in the manner described in Example lg to form 21 -acetoxy-11 ,17aa-di hydroxy- 17a-methyl -D-homo-pregn-4-en-3 ,20-dione .

Chromatography of the crude product yields ll ,17aa-dihydroxy-21-acetoxy-17a-methyl-D-homo-4-pregnen-3,20-dione melting at 210-212°C (from ethyl acetate).

Example 23 2 g of 33,ll3,17a -trihydroxy-17a-methyl-D-homo-pregn-5-en-20-one in 20 ml of cyclohexanone and 60 ml of toluene are heated to the boil. 10 ml of the solvent is distilled off. To the mixture cooled to about 5°C are added 2 g of aluminium tri-tertiary butyl ate. The reaction mixture is then boiled for 1 hour under a water separator. After cooling, the mjxture is poured on to dilute aqueous acetic acid and extracted with methylene chloride. The methylene chloride solutions are washed with water, dried and evaporated. The poorly volatile constituents are distilled off under a high vacuum up to a temperature of about 140°C. The residue is purified by chromatography. There is obtained ll3,17aa-dihydroxy-17a-methyl-D-homo-pregn-4-en-3,20-dione Example 24 (a) 3e,lla-D hydroxy-5-androsten-l-one is reacted with dimethyl -sulphoxoni urn, methyl de in di methyl formamide to form 33, Πα-di hydroxy-! 7, 20-epoxy-21-nor-5- pregnen-melting at 190-193°C.

The epoxide so obtained is reacted in an autoclave with alcohol and concentrated ammonia to form 17-aminomethyl-3$,lla>17-trihydroxy-5-androstene, which upon treatment with sodium nitrite in dilute acetic acid forms 3$,lla- dihydroxy-D-homo-5-androsten-17a-one melting at 200-201°C.

This D-homo-compound is reacted in liquid ammonia with potassium acetylide, and 3β,1 la »17a-tri hydroxy-! 7a-eth nyl-D-homo-5-androstene melting at 204-205°C is obtained.

This ethinyl -compound is esterified with acetic anhydride in pyridine at room temperature, and 17a-hydroxy-33,lla-diacetoxy-17a-ethinyl-D-homo-5-androstene melting at 208-211 °C is obtained.

The diacetox ycompouhd so obtained is reacted in 2,4-lutidine with phosphorus oxychloride at 120°C for 20 hours, and 3g,lla-diacetoxy-17a-ethinyl- D-homo-5,17-androstadiene is obtained in the form of a colourless oil.

The androstadiene is reacted with mercury para-toluene sul phonic acid amide in aqueous ethanol to form 3g,lla-diacetoxy-D-homo-5,17-pregnadien-20-one 'melting at 216-217°C.

The di acetate so obtained^ reacted with sodium carbonate in methanol, and 3g-hydroxy-lla-acetoxy-D-homo-5,17-pregnadien-20-one melting at 220-222°C is obtained, which after oxidation by the Oppenauer method yields 1 la-acetoxy-D homo-4,17-pregnadien-3,20-dione melting at 147-148°C.

The compound so obtained is reacted in ether/pyridine with osmium, tetroxide to form 17a J7aa-dihydroxy-lla-acetoxy-D-homo-4-pregnen-3,20-dione (melting at 231-232°C), which by reaction with acetone in the presence of perchloric acid forms Ha-acetoxy-17a»17aa-isopropylidene3ioxy-D-homo-4-pregnen-3,20-dione melting at 198-200°C.

The lla-acetoxy-compound so obtained is hydrolysed in a methanol ic solution of potassium hydroxide at room temperature, and 1 la- hydro xy-17a,l 7aa- (b) A solution of 2.15 g of 1 la-hydroxy-17a ,17a - i sopropyl - -idene-dioxy-D-homo-pregn-4-en-3,20-dione and 2.2 ml of methanesul phochloride in 20 ml of pyridine is maintained at 0°C for 3 hours. The reaction mixture is poured on to ice-water, and extracted with ethyl acetate. The organic extracts are washed with dilute hydrochloric acid, water, sodium carbonate and again with water, then dried with sodium sulphate and evaporated to dryness in vacuo. The residue is dissolved in 100 ml of dimethyl formami de , g of lithium chloride are added, and the whole is heated for 90 minutes at 100°C. For working up, the mixture is poured into 500. ml of ice-water and extracted with methylene chloride. The extract is washed with dilute hydrochloric acid, water sodium carbonate solution and water, dried with sodium sulphate, and evaporated i n vacuo . The residue is chromatographed over silica gel . The unitary fracti eluted with ether-hexane (1 :1 ) after thin layer chromatography are combined and recrystall iaed from acetone-hexane . There is obtained pure 17a ,17aa-i sopropyl i denedioxy-D-home-pregna-4,9(ll )-dien-3 ,20-dione melting at 150-151°C. (c) Under the conditions described in Example lib the 17ct,17aa i sopropyl -i denedi oxy-D-homo-4 ,9(11 )-pregnadien-3,20-dione is reacted with N-chlorosuccinimide and perchlori acid and 9a-chl oro-11 -hydroxy-l 7a, 17 aa-i sopropyl i denedi oxy-D-homo-4-pregnen-3 ,20-dione is obtained. 45738/2 Example 25 800 mg of 11 ,21 -di hydroxy-! ,4-pregnadi en-3 ,20-dione are dissolved in 8 ml of di methyl formami de , 1.6 ml of acetic anhydride and 112 mg of lead diacetate are added, and the whole is stirred for 2 hours at room temperature. The mixture is then precipitated in ice-water, the product is filtered off with suction, washed with water and dried. After recrystal 1 i sati on from acetone-hexane there are obtained 820 mg of 11 β- hydroxy- 21 -acetoxy-D-homo-1 ,4-pregnadi en-3, 20-dione melting at 192-193°C.

Example 26 700 mg of 21 -acetoxy-9a-f 1 uoro-113-hydroxy-D-homo-pregna-1 ,4-di en-3 ,20-di one are hydrolysed and worked up in a manner analogous to that in Example 6. After recrystal 1 i sati on from acetone-hexane, there are obtained 587 mg of 9a-f 1 uoro-11 B ,21 -di hydroxy-D-homo-pregna-1 ,4-di en-3 ,20-di one melting at 197-199°C.

Example 27 150 mg of 21 -acetoxy-D-homo-pregna-1 ,4 ,9 ( 11 ) -tri en-3,20-dione are introduced at 0°C into a solution of 1.5 ml of dimethyl formami de , 1.5 ml of hydrogen fluoride and 60 mg of N-chl orosucci ni mi de , and the whole is stirred for 40 hours at 0°C. The solution is then poured into an ice-cold solution of potassium 1 ·. I acetate, the precipitated reaction product is filtered off with suction, > and recrystallised from acetone-hexane. There are obtained 95 mg of 9a-chloro-llg-fluoro-21-acetoxy-D-homo-l ,4-pregna-dien-3,20-dione melting at 169-170°C.

Example 28 A 2-litre Erlenmeyer flask, which contains 500 ml of a nutrient solution sterilized in an autoclave for 30 minutes at 120°C and consisting of 1% of corn steep liquor, 1% of soya bean powder and 0.005% of soya bean oil, adjusted to a pH value of 6.2, is inoculated with a lyophilic culture of Curvularia lunata (NRRL 2380), and is agitated for 72 hours at 30°C on a rotary agitator. With this precUlture is inoculated a 20-litre fermenter, which contains 15 1 of a medium sterilized at 121°C and 1.1 atmospheres gauge consisting of 1% of corn steep liquor, 0.5% of starch sugar and 0.005% of soya bean oil, adjusted to a pH-value of 6.2. With the addition of silicone SH as anti-foaming agent germination is carried out at 29°C while aerating (10 litres/minute), under a pressure of 0.7 atmospheres gauge and while stirring (220 revolutions per minute) for 24 hours. 1 Litre of the culture liquor is transferred under sterile conditions to 14 1 of a medium sterilized as above and consisting of l¾ of corn steep liquor, 1.2% of soya bean powder and 0.005% of soya bean oil, and grown under the same conditions. After 6 hours, a solution of 6 g of 21-acetoxy-D-homo-4-pregnen-3,20-dione in 300 ml of dimethylsulphoxide are added.

After a contact time of 44 hours the contents of the fermenter are extracted by stirring twice with 10 1 of methyl isobutyl ketone each time, and the extract is evaporated in vacuo at a bath temperature of 50°C. The once again with hexane in order to remove the silicone oil residue is washed watb-bexane,, and converted by digestion with acetone/ isopropyl ether into a crystalline crude product (3.1 g), which is used in this form for a subsequent dehydrogenation.

A test sample of the crude product was recrystallised from acetone/ ether to form ll3,21-dihydroxy-D-homo~4-pregnen-3,20-dione melting at 188/191-195°C.

Example 29 A 2-litre Erlenmeyer flask, which contains 500 ml of a nutrient solution sterilized in an autoclave for 30 minutes at 120°C and consisting of 1.5% of peptone, 1.2% of corn steep and 0.2% of MgSO^, adjusted to a pH-value of 6.5, is inoculated with a lyophilic culture of Bacillus lentus (ATCC 13805) and agitated for 24 hours at 30°C. With this preculture is inoculated a 20-litre fermenter, which contains 15 1 of a liquid nutrient medium sterilized at 121 °C and 1.1 atmospheres gauge and consisting of 0.2% of yeast extract, 1% of corn steep liquor and 0.1% of starch sugar, adjusted to a pH-value of 7.0. With the addition of silicone SH as anti foaming agent germination is carried out at 29°C while aerating and stirring. After a growth phase of 6 hours, a solution of 6 g of 113,21-dihydroxy-D-homo-4-pregnen-3,20-dione in 100 ml of dimethyl formamide is added.

After a contact time of 42 hours, the contents of the fermenter are extracted twice with 10 1 of methyl isobutyl ketone each time, and the extract is evaporated in vacuo. The residue is washed with hexane to remove the silicone oil, and, after treatment with active carbon in methanolic solution recrystallised twice from acetone/ether to yield 3 g of ll$,21-dihydroxy-D-homo-1 ,4-pregnadien-3,20-dione melting at 170/173-174°C.

Example 30 320 mg of 9S,ll£-epoxy-21-acetoxy-D-homo-l .4-pregnadiene-3,20-dione is dissolved in 2 ml of dimethyl formamide and added at -20°C to a solution of 2 ml dimethyl formamide and 2 ml of hydrogen fluoride. The mixture is stirred at room temperature for 19 hours, than poured in on ice-cold solution of potasium acetate. The precipitated reaction product is filtered off with suction, recrystallised from acetone and 168.8 mg of 9 -fluoro-ll -hydroxy-21-acetoxy-D-homo-l ,4-pregnadiene-3,20-dione are obtained.

Melting point 227-228°G.

Example 31 a ) 11 ,17aa-di hydroxy-21 -acetoxy-D-homo-1 ,4-pregnadi ene-3 ,20-dione is reacted with methanesulfochloride in sulfur dioxide to yield the 21 -acetoxy-D-homo-1 ,4,9(11 ) ,17-pregnatetraene-3,20-dione. Meltiing point 165-166°C.

The tetraene is reacted in dioxan with N-bromoacetamide and aqueous perchloric acid to yield the 9a-bromo-113-hydroxy-21 -acetoxy-D-homo-1 ,4,17 pregnatriene-3,20-dione. Melting point 193-195°C.

The bromohydrine is reacted in boiling ethanol with potasium acetate to yield the 93-113-epoxy-21 -acetoxy-D-homo-1 ,4,17-pregnatriene-3,20-dione. Melting point 166-167°C.

The epoxyde is reacted with hydrogen fluoride as described in Example 30 to yield the 9a-fluoro-113-hydroxy-21 -acetoxy-D-homo-1 ,4,17-pregnatriene-3,20-dione melting at 213-214°C. b) 1 g of 9a-fluoro-113-hydroxy-21-acetoxy-D-bomo-l ,4-pregnatriene-3,20-dione is oxidised with 730 ml osmium tetroxide as described in Example 21 and 600 mg of 9a-f luoro-11 -17 -17act-tri hydroxy-21 -acetoxy-D-homo-1 ,4-pregnadiene-3,20-dione are obtained. Melting point 265-266°C.

Example 32 500 mg of 9a-fluoro-113-17a,17aa-trihydroxy-21-acetoxy-D-homo-l ,4 pregnadiene-3,20-dione are dissolved in 25 ml of acdtone, two drops of perchloric acid of 70% strength are added and the mixture is stirred at room temperature for 24 hours. Then 0,5 ml of saturated aqueous sodium bicarbonate solution are added, the mixture concentrated in vacuo, and the residue dissolved in methylene chloride. The methylene chloride solution is washed and concentrated and the residue is purified by chromatography over a column of silica gel. There are obtained after recrystallisation from acetone-hexane 160 mg ^a-fluoro-llB-hydroxy-17 ,17aa-isopropylidenedioxy-21 -acetoxy-D-homo-1 ,4-pregnadi ene-3, 20-di one which melts at 205-207°C.

I. Pharmaceutical preparations Example 1 The composition of a salve: ,01 % of 6ot -f 1 uoro-113-hydroxy-21 -acetoxy-T7 -methyl -D-homo-l ,4- pregnadien-3,20-dione f5 % of Allercur hexachlorophenate, micronised, particle size about 8 (Allercur = registered Trade Mark for 1-para- chl orobenzyl -2-pyrrol i dyl -methyl -benzimi dazol e ) .

R .00% of Hostaphat KW 340 (tert. ester of ortho-phosphoric acid and wax alcohol tetraglycol ether) .10% of sorbic acid .00% of neutral oil (Migloyol 812R) .50% of stearyl alcohol .50% of wool fat, anhydrous DAB 6 .39% of desalted water. -43b- Example 2 The composition of a salve: 0.01 grams of 6a-fluoro-9a-chloro-llB-hydroxy-21-acetoxy-17a-methyl-D- homo-1 ,4-pregnadien-3,20-dione .00 grams of white wax DAB 6 .00 grams of wool fat, anhydrous DAB 6 .00 grams of white petroleum jelly DAB 6 .00 grams of Amphocerin K "Dehydag" 14.97 grams of paraffin oil, liquid DAB 6 .00 grams of water, desalted 0.02 grams of Crematest perfume oil No. 6580 "Dragee".

Example 3 The composition of eye drops (oily): 100 mg of 6a-fluoro-ll3-hydroxy-21-acetoxy-l 7 -methyl -D-homo-1 ,4- pregnadien-3,20-dione are dissolved in 100 ml of castor oil.

After the addition of 200 mg of chloramphenicol (or another bacteriostatic), the solution is filtered sterile, and bottled aseptically.

Example 4 The composition of ear drops: 100 mg of βα-fl uoro-ll0-hydroxy-21-acetoxy-17a-methyl -D-homo-1 ,4- pregnadien-3,20-dione are dissolved in 1 ,2-propylene glycol/ethyl alcohol (9:1 ) . To the solution made up to 100 ml are then added 200 mg of chloramphenicol.

Example 5 The composition of a salve: 0.10 grams of sodium-(9a-fluoro-ll$-hydroxy-3,20-dioxo-17a-methyl-D-homo- 1 ,4-pregnadien-21-yl )-sulphate 45.00 grams of white Vaseline petroleum jelly raw .00 grams of high molecular mixed esters of near^natural -rart- materials 0.02 grams of perfume oil .00 grams of water.

Example 6 The composition of a cream: 0.10 grams of disodium (6a-fluoro-113-hydroxy-3,20-dioxo-17a-methyl- D-homo-1 ,4-pregnadien-21-yl ) phosphate 3.00 grams of polyoxyl stearate 7.50 grams of paraffin (thickly liquid) 7.50 grams of white petroleum jelly 8.50 grams of glycerine mono- and di-stearate 3.50 grams of stearyl alcohol 0.07 grams of para-hydroxybenzoic acid methyl ester 0.02 grams of perfume oil 69.78 grams of water.

Example 7 The composition of a tablet: 0.250 mg of 9a-fluoro-ll6-hydroxy-21-acetoxy-D-homo-l ,4-pregnadien- 3,20-dione 36.000 mg of lactose DAB 6 75.780 mg of maize starch USP XVI 0.500 mg of sodium lauryl sulphate (Texapon K 12) "Dehydag", USP XVI 1.400 mg of gelatine, white DAB 6 6.000 mg talcum DAB 6 0.024 mg Nipagin M (para-oxybenzoic acid methyl ester) DAB 6, 3rd supplement 0.011 mg of Nipasol M (para-oxybenzoic acid propyl ester) DAB 6. 3rd supplement 0.035 mg of dyestuff pistachio green "Dragoco" Example 8 The composition of a tablet: 0.025 mg of 6a,9 -difluoro-l l3-hydroxy-21-acetoxy-17a-methyl-D-homo- 1 ,4-pregnadien-3,20-dione 36.475 mg of lactose DAB 6 75.530 mg of maize starch USP XVI 0.500 mg of sodium lauryl sulphate (Texapon K 12) "Dehydag" USP SVI 1.400 mg gelatine, white DAB 6 6.000 mg of talcum DAB 6 0.024 mg of Nipagin M (para-oxybenzoic acid methyl ester) DAB 6, 3rd supplement 0.011 mg of NipasoT "M (para oxybenzoic- acid propyl ester) DAB 6 3rd 0.035 mg of dyestuff pistachio green "Dragoco" supplement.

Example 9 The preparation of an injection solution: 50 mg of 6 -fluoro-9 -chloro-ll3-hydroxy-21-acetoxy-17a-methyl-D-homo-1 ,4-pregnadien-3,20-dione are dissolved in 10 ml of sesame oil, and the solution is charged into ampoules of 1 ml capacity and sterilized in the usual manner.

The preparation of an inhalant preparation: 1000 grams of micronised 6a-fluoro-ll3-hydroxy-16a-methyl-D-homo- 1 ,4-pregnadien-3,20-dione (average particle size smaller than 7μ) and 39.000 grams of ground lactose are mixed together. Every 40 mg of the mixture are charged into plug capsules.

The inhalant preparation may be administered by opening the (R) capsule and inhaling, preferably by sniffing, or a Spinhaler ' is used for administering the inhalant preparation,

Claims (1)

1. 45738/2 -homo-steroids of the general formula in which the bond ...... is a single bond or a double bond, X represents a hydrogen atom, or a fluorine atom, Y represents a hydrogen atom or a fluorine atom, and Z represents a hydroxyl group or Y represents a chlorine atom and Z a hydroxyl group, a fluorine atom or a chlorine atom, R.j represents a hydrogen atom, a free hydroxyl group or one esterified with a lower al kanoyl^ s ul phate or phosphate group and i n whi ch Rg represents a hydrogen atom or a methyl group, R^ represents a hydroxyl group^ R^ represents a* methyl group or a hydroxyl group^ R5 represents a lower alkyl group, and Re represents a lower alkyl group. - 47 - 2. ll3>21-Dihydroxy-17a-methyl-D-homo-4-pregnen-3,20-dione. •2^3. 11 ,21 -Dihydroxy-17a-methyl -D-homo-l ,4-pregnadien-3,20-dione. 3 4. ll3-Hydroxy-21 -butyroxy-17a-methyl^D-homo-l ,4-pregnadien-3,20-dione. 5. ll3-Hydroxy-21-acetoxy-17a-methyl -D-homo-l ,4-pregnadien-3,20-dione. ^ 6. 9a-Fluoro-ll3-hydroxy-21-acetoxy-17a-methyl -D-homo-l ,4-pregnadien-3,206dione. CI . 9a-Fluoro-ll 3, 21 -di hydroxy-! 7a-methyl -D-homo-l ,4-pregnadien-3,20-dione. 8. Sodium-[9a-fluoro-ll3-hydroxy-3,20-dioxo-17a-methyl-D-homo-l ,4- pregnadien-21-yl]-sulphate. ? 9. 6a-Fluoro-ll3,21-dihydroxy-17a-methyl-D-homo-4-pregneri-3,20-dione. 10. 6a-Fluoro-ll3,21-dihydroxy-17a-methyl-D-homo-l ,4-pregnadien-3,20-dione. rt 11. 6a-Fluoro-ll3-hydroxy-21-acetoxy-17a-methyl -D-homo-l ,4-pregnadien-3,20-dione. 12. 6a-Fl uoro-9 -chl oro-11 g-hydroxy-21 -trimethyl -acetoxy-17a-methyl -D-homo- 1 ,4-pregnadien-3,20-dione. Ή3. 6a-Fluoro-9 -chl oro-1 l3-hydroxy-21 -acetoxy-17a-methyl -D-homo-l ,4-pregnad en- 3,20-dione. fi 14. 6a ,9a-Difluoro-ll3-hydroxy-21 -acetoxy-17a-methyl -D-homo-l ,4-pregnadi en- 3,20-dione. 15. 6a,9a-Difluoro-ll , 1 -dihydroxy-17a-methyl -D-homo-l ,4-pregnadien-3,20-dione. ( i 6. 6a- Fl uoro-9a , 113-di chl oro-21 -acetoxy-17a-methyl -DGhomo-l ,4-pregnadi en- 3,20-dione. 17. 6a .113-Di f 1 uoro-9a-chl oro-21 -acetoxy-17a-methyl -D-homo-l ,4-pregnadi en- 3,20-dione. if-18. Disodium (6a-fluoro-ll3-hydroxy-3,20-dioxo-17a-methyl-D-homo-l ,4- pregnadien-21-yl ) phosphate. 19. 6a-Fl uoro-11 ,21 -di hydroxy-D-homo-4-pregnen-3 ,20-di one . (»520. 11 ,21 -Di hydroxy-17a-methyl -D9homo-4-pregnen-3 ,20-dione. 21. 6a-Fluoro-ll3-hydroxy-21-acetoxy-17a-methyl-D-homo-4-pregnen-3,20-dione. l]22. ll3,17a,17aa,21-Tetrahydroxy-D-homo-4-pregnen-3,20-dione. .23. 11 ,17aa-Di hydroxy-21 -acetoxy-17a-methyl -D-homo-4-pregnen-3 ,20-dione . ^24. 11 ,17a -Di hydroxy-17a-methyl -D-homo-4-pregnen-3 ,20-dione . Z 25. 9a-Chloro-ll3-hydroxy-17a-jl7a -isopropylidenedioxy-4-pregnen-3,20-dione. I 26. Process for the manufacture of D-homo-steroids of the general formula I in which the bond ........ is a single bond or a double bond, or X represents a hydrogen atom, /a fluorine atom,er-a-ffle*hy4-§*Oyp-, Y represents a hydrogen atom or a fluorine atom, and Z represents a hydroxyl group or Y represents a chlorine atom and Z a hydroxyl group, a fluorine atom or a chlorine atom, in which R2 represents a hydrogen atom or a methyl group, R~ represents a hydroxyl group tM^-ati-a-e ^f^y-^rewp, or R4 represents a methyl group, /a hydroxyl group w-^^l^-^aup-, Rc represents a- -hyd«§efl--a-tem- -or a lower alkyl group, and Rg represents a lower alkyl group <>-^-+>e^-^oo-> characterised in that in a manner in itself known (a) hypochlorous acid, hypobromous acid, chlorine or fluorine and chlorine is additively combined at the ^-double bond of a compound of the general formula II in which X, -A-B,^^ and R.j have the meanings given for formula I, optionally the resulting llg-hydroxy-9a-halogen-steroids are converted by treatment with bases into the corresponding 9R,ll3-epoxy-steroids, and then the epoxide ring is opened up with hydrogen fluoride or hydrogen chloride or an additively combined bromine atom in the 9a-position is reductively eliminated, or (b) a compound of the general formula III :H2R in which X, Y, Z, -A-B ^ and R- have the meanings given for formula I, and R-, represents a hydrogen atom or a lower acyl residue, is oxidized 4 to the corresponding 3-keto-A -steroid, optionally after hydrolysis of the 3-acyloxy group, (c) HV is split off from a compound of the general formula IV in which Χ,Υ,Ζ, -A-B ^and R. have the meanings given for formula I, and V represents a hydroxyl group or a bromine atom, or (d) for preparing a D-homo-steroid of the general formula I in which Y represents a hydrogen atom, a compound of the generai formula V CH2R in which X, -A-B ^ and have the meanings given for formula I, is hydroxylated in the ll-position by means of llp-hydroxylating micro-organisms, (e) in a compound of the general formula VI C=0 in which X, Y, Z and -A-B^ have the meanings given for formula I, and W represents an alkyl-sul phony! oxy group, an aryl-sulphonyloxy group, a bromine atom or an iodine atom, the substituent W is exchanged for a hydrogen atom, e-f½eHfle-at€m-,-fl-eHeHne-etonr, an alkanoyloxy aey ex group or a phosphate residue, or (f) for preparing D-homo-steroids of the general formula I in which Rg and R^ represents a hydrox 1 group, additively combining hydroxy 1 17 groups at the Δ -double bond of a compound of the general formula VII in which X, Y, 2. and R. have the meanings given for formula I, or (g) for preparing Ijf-methyl -D-homo-steroids of the general formula I, a compound of the general formula VIII in which X, Y, Z and R-j have the meanings given for formula I, and U represents an alkylene residue i$or a phenylene residue, is reacted with a methyl magnesium halide or lithium-copper dimethyl, optionally the 20-oxo group is converted by reaction with acyl chlorides or acyl bromides into the 20-enol-acylate, the latter is epoxidised with per-acids, and then the reaction product so obtained is hydrolysed by treatment with 4 acid, optionally D-homo-Δ -steroids of the general formula I obtained by the process variants (a) to (g) are dehydrogenated in the 1,2-position and/or ester groups or ketal groups present are split off by hydrolysis and/or hydroxyl groups present are esterified or condensed with carbonyl compounds of the general formula R-.RgC0, in which R^ and Rg have the meanings given above. 27. A pharmaceutical preparation comprising the content of D-homo-steroids of the general formula I in which the bond is a single bond or a double bond, or X represents a hydrogen atom,/ a fluorine atom or-a-methy†-groap, Y represents a hydrogen atom or a fluorine atom, and Z represents a hydroxyl group or Y represents a chlorine atom and Z a hydroxyl group, a fluorine atom or a chlorine atom, R, represents a hydrogen atom, a-flueicine-atom,-a-CBlQPine-ateffl-eF-a-fFee- a free hydroxyl group or one esterified with a lower alkanoyl, sulphate er-esteptfted-hydpewl-gpeip-aRd- or phosphate groups, and in which f*2 represents a hydrogen atom or a methyl group, Rg represents a hydroxyl group, R^ represents a methyl group or a hydroxyl group or Rg represents a lower alkyl group, and Rg represents a lower alkyl group, in admixture or conjunction with a pharmaceutically suitable carrier. 28. 11 e-Hydroxy-21 -acetoxy-D-homo-1 ,4-pregnadien-3,20-dione 29. 9a-Fl uoro-113-hydroxy-21-acetoxy-D-homo-l ,4-pregnadien-3,20-dione. 30. 9a-Fluoro-113,21-Dihydroxy-D-homo-l ,4-pregnadi en-3 ,20-dione . 31. 9a-Chl oro-113- 1 uoro- 21 -acetoxy-D-homo-1 ,4-pregnadien-3,20-dione. 32. 113 ,21 -Di hydroxy-D-homo-4-pregnen-3 ,20-di one . 33. 11 .21 -Di hydroxy-D-homo-1 ,4-pregnadi en-3 ,20-di one . For the Applicants Wolff, Bregman and Goller